Patent Application
20080057084
The following drawings are presented to assist understanding of aspects and features of the present invention.
The present invention is based on the discovery that a headache such as a migraine headache can be by treated by selecting for patients with imploding headache (i.e. an outside to inside pain perception) and/or ocular headache (as opposed to selecting patients with exploding headache (i.e. an inside to outside pain perception). Concomitantly, the present invention is based on the discovery that a headache such as a migraine headache can be by treated by selecting for treatment those patients who do not predominantly have or who do not have at all an exploding headache (i.e. an inside to outside pain perception).
We have found that patients who have imploding and/or ocular headache pain respond well to treatment with a botulinum toxin, whereas patients who have exploding headache do not respond well to treatment with a botulinum toxin.
A patient with a headache (such as a migraine headache) for whom administration of a botulinum toxin results in alleviation of a symptom (such as a pain symptom) of the headache can be referred to as a responder. Similarly, a patient with a propensity or a predisposition to experience headaches (such as migraine headaches) for whom administration of a botulinum toxin results in a prophylactic reduction in the number, duration and/or intensity of the headaches experiences can also referred to as a responder.
A patient with a headache (such as a migraine headache) for whom administration of a botulinum toxin does not result in a significant or substantial alleviation of a symptom (such as a pain symptom) of the headache can be referred to as a non-responder. Similarly, a patient with a propensity or a predisposition to experience headaches (such as migraine headaches) for whom administration of a botulinum toxin does not result in a significant or substantial prophylactic reduction in the number, duration and/or intensity of the headaches experiences can also referred to as a non-responder.
Thus, as shown by
It is important to note that the method of administration of a botulinum toxin (including the characteristics of fixed site dose, follow the pain dosing, multiple sites, single site, high dose or low dose) are not important or significant characteristics of our invention. The significant characteristic of our invention is to select (for administration of a botulinum toxin to treat a headache and/or to prevent development of a headache) for a patient who has an imploding headache and not select a patient who has an exploding headache. We have found that a patient who has an imploding headache pain show a greater reduction in headache pain and/or in the number of headache free days (upon administration of a botulinum toxin using a fixed site dose, follow the pain dosing, multiple sites, single site, high dose or low dose of the botulinum toxin) than will a patient who has an exploding headache pain.
A headache can be treated by local administration of a therapeutically effective amount of a botulinum toxin. Thus, a botulinum toxin (such as a botulinum toxin serotype A, B, C1, D, E, F or G) can be injected (i.e. intramuscular injection) into or in the vicinity where a patient is experiencing the pain to thereby suppress the pain or prevent its occurrence. Alternately, the botulinum toxin can be administered to an intradermal or subdermal pain sensory neuron thereby suppressing and treating a headache.
We have developed a method for treating a patient with a headache with a botulinum toxin with a high probability that the patient will respond to the botulinum toxin, that is that a symptom of his headache will be alleviated. This treatment method is base upon a method for selecting for treatment patients who are responders. According to our invention, patients who are determined to be non-responders are not administered a botulinum toxin to treat their headache.
Responders are selected for by determining if the patient has an imploding headache or an exploding headache. We found that in a group of 34 patients with imploding headache 32 (91%) responded to administration of a botulinum toxin. On the other hand in a separate group of 27 patient with exploding headache we found that 24 (92%) did not respond to administration of the botulinum toxin. Thus, we determined that patients with imploding headache are responders, whereas patients with exploding headache are non-responders.
Various injection techniques can be used to treat a headache with a botulinum toxin. For example single or multiple injections have been used. Additionally, the botulinum toxin injection can be at a fixed site or sites or a “follow the pain” (injections tailored to the sites where the patient perceives the pain to arise from). See eg. Kriegler J., et al., Single site Botox™ injection: Effective treatment for migraine headaches, Headache 2006 May; 46(5):849; LaButta R., et al., Effectiveness of botulinum toxin type-A in the treatment of migraine headache: A randomized controlled trial, Neurology 2005 March; 64(Suppl 1), and; Crnac, M., et al., Individual injection scheme in the treatment of headache with botulinum toxin, J Neurol 2004; 251 (Suppl 1):I/43 A9.
For example, a botulinum toxin can be administered intramuscularly in an average of up to 20 separate injections to each patient. The botulinum toxin can be administered at up to seven different muscles (i.e. 20 total injections into 7 muscles). From example, about 100 to 300 units of a botulinum toxin such as BOTOX can be administered to a patient.
The botulinum toxin (i.e. Botox) can be administered (23-58 injections of 105-260 units in 6-7 muscle areas) determined based on the pain distribution pattern and the severity of pain in the particular muscle area of the patient. The patient can be injected in one or more of 6 muscle areas; frontal/glabellar, occipitalis, temporalis, semispinalis, splenius capitis, and trapezius muscles, as shown in Table 1 and the
Administration of a botulinum toxin to a head, neck or shoulder location may act to block extracranial nerves which act to rely sensory (pain) signals from the meninges, bone and scalp to a central (CNS) location, as illustrate by
Significantly, it has been determined that a botulinum toxin can act to reduce transmission of sensory information from muscle type la afferent neurons. Aoki, K., Physiology and pharmacology of therapeutic botulinum neurotoxins, in Kreyden, O., editor, Hyperhydrosis and botulinum toxin in dermatology, Basel, Karger; 2002; 30: pages 107-116, at 109-110. And it has been hypothesized that botulinum toxin can have a direct effect upon muscle cell sensory afferents and modify signals from these afferents to the central nervous system. See e.g. Brin, M., et al., Botulinum toxin type A: pharmacology, in Mayer N., editor, Spasticity: etiology, evaluation, management and the role of botulinum toxin, 2002; pages 110-124, at 112-113; Cui, M., et al., Mechanisms of the antinociceptive effect of subcutaneous BOTOX®: inhibition of peripheral and central nociceptive processing, Naunyn Schmiedebergs Arch Pharmacol 2002; 365 (supp 2): R17; Aoki, K., et al., Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions, Eur J. Neurol 2001: (suppl 5); 21-29. Thus, it has been demonstrated that botulinum toxin can cause an altered sensory output from muscle to CNS and brain.
Importantly, the sensory neurons from which afferent output is to be inhibited by a method according to the present invention need not be located on or within a muscle, but can be in an intradermal or subdermal location.
Thus, pain can be due to sensory input from afferent facial area neurons. Administration of a botulinum toxin to a facial muscles or skin to reduce sensory output from the muscle can result in alleviation of and prevention of pain.
Our invention also includes a method for treating an ocular headache, such as an ocular migraine headache by administration of a botulinum toxin by infusing the botulinum toxin behind the globe of the eye to target C and A-delta pain fibers present in this peri-bulbar location in the skull, thereby following the neural innervation.
The amount of the botulinum toxin administered according to a method within the scope of the disclosed invention can vary according to the particular characteristics of the pain being treated, including its severity and other various patient variables including size, weight, age, and responsiveness to therapy. To guide the practitioner, typically, no less than about 1 unit and no more than about 70 units of a botulinum toxin type A (such as BOTOX® is administered per injection site (i.e. to each muscle portion injected), per patent treatment session. For a botulinum toxin type A such as DYSPORT®, no less than about 4 units and no more about 280 units of the botulinum toxin type A are administered per injection site, per patent treatment session. For a botulinum toxin type B such as MYOBLOC®, no less than about 40 units and no more about 2800 units of the botulinum toxin type B are administered per injection site, per patent treatment session. Less than about 1, 4 or 40 units (of BOTOX®, DYSPORT® and MYOBLOC® respectively) can fail to achieve a desired therapeutic effect, while more than about 70, 280 or 2800 units (of BOTOX®, DYSPORT® and MYOBLOC® respectively) can result in significant muscle hypotonicity, weakness and/or paralysis.
More preferably: for BOTOX® no less than about 5 units and no more about 60 units of a botulinum toxin type A; for DYSPORT® no less than about 20 units and no more than about 240 units, and; for MYOBLOC®, no less than about 200 units and no more than about 2400 units are, respectively, administered per injection site, per patent treatment session.
Most preferably: for BOTOX® no less than about 10 units and no more about 50 units of a botulinum toxin type A; for DYSPORT® no less than about 40 units and no more than about 200 units, and; for MYOBLOC®, no less than about 400 units and no more than about 2000 units are, respectively, administered per injection site, per patent treatment session. It is important to note that there can be multiple injection sites (i.e. a pattern of injections) for each patient treatment session.
Generally, the total amount of BOTOX®, DYSPORT® or MYOBLOC®, suitable for administration to a patient according to the methods of the invention disclosed herein should not exceed about 300 units, about 1,500 units or about 15,000 units respectively, per treatment session. For XEOMIN® (a 150 kDa botulinum toxin type A formulation available from Merz Pharmaceuticals, Potsdam, Germany) about 1× to about 2× the amounts of BOTOX® set forth above can be used in each instance.
When BOTOX® is administered, each vial of BOTOX® contains 100 units of Clostridium botulinum toxin type A (purified), 0.5 mg albumin (human), and 0.9 mg sodium chloride in a sterile, vacuum-dried form without a preservative. One unit corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice. Preferably, the vials are stored in a freezer between −20° C. and −5° C. before use. Reconstitution is with 0.9% sterile saline (without preservatives) for injection.
Examples of Clostridial toxins within the scope of the present invention include neurotoxins made by Clostridium botulinum, Clostridium butyricum and Clostridium beratti species. In addition, the botulinum toxins used in the methods of the invention may be a botulinum toxin selected from a group of botulinum toxin types A, B, C, D, E, F, and G. In one embodiment of the invention, the botulinum neurotoxin administered to the patient is botulinum toxin type A. Botulinum toxin type A is desirable due to its high potency in humans, ready availability, and known use for the treatment of skeletal and smooth muscle disorders when locally administered by intramuscular injection. The present invention also includes the use of (a) Clostridial neurotoxins obtained or processed by bacterial culturing, toxin extraction, concentration, preservation, freeze drying, and/or reconstitution; and/or (b) modified or recombinant neurotoxins, that is neurotoxins that have had one or more amino acids or amino acid sequences deliberately deleted, modified or replaced by known chemical/biochemical amino acid modification procedures or by use of known host cell/recombinant vector recombinant technologies, as well as derivatives or fragments of neurotoxins so made. These neurotoxin variants retain the ability to inhibit neurotransmission between or among neurons, and some of these variants may provide increased durations of inhibitory effects as compared to native neurotoxins, or may provide enhanced binding specificity to the neurons exposed to the neurotoxins. These neurotoxin variants may be selected by screening the variants using conventional assays to identify neurotoxins that have the desired physiological effects of inhibiting neurotransmission.
Botulinum toxins for use according to the present invention can be stored in lyophilized, vacuum dried form in containers under vacuum pressure or as stable liquids. Prior to lyophilization the botulinum toxin can be combined with pharmaceutically acceptable excipients, stabilizers and/or carriers, such as albumin. The lyophilized material can be reconstituted with saline or water to create a solution or composition containing the botulinum toxin to be administered to the patient.
Although the composition may only contain a single type of neurotoxin, such as botulinum toxin type A, as the active ingredient to suppress neurotransmission, other therapeutic compositions may include two or more types of neurotoxins, which may provide enhanced therapeutic treatment of a headache. For example, a composition administered to a patient may include botulinum toxin type A and botulinum toxin type B. Administering a single composition containing two different neurotoxin's may permit the effective concentration of each of the neurotoxins to be lower than if a single neurotoxin is administered to the patient while still achieving the desired therapeutic effects. The composition administered to the patient may also contain other pharmaceutically active ingredients, such as, protein receptor or ion channel modulators, in combination with the neurotoxin or neurotoxins. These modulators may contribute to the reduction in neurotransmission between the various neurons. For example, a composition may contain gamma aminobutyric acid (GABA) type A receptor modulators that enhance the inhibitory effects mediated by the GABAA receptor.
The botulinum neurotoxin may be administered by any suitable method as determined by the attending physician. The methods of administration permit the neurotoxin to be administered locally to a selected target tissue. Methods of administration include injection of a solution or composition containing the neurotoxin, as described above, and include implantation of a controlled release system that controllably releases the neurotoxin to the target tissue. Such controlled release systems reduce the need for repeat injections. Diffusion of biological activity of a botulinum toxin within a tissue appears to be a function of dose and can be graduated. Jankovic J., et al Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page 150. Thus, diffusion of botulinum toxin can be controlled to reduce potentially undesirable side effects that may affect the patient's cognitive abilities. For example, the neurotoxin can be administered so that the neurotoxin primarily effects neural systems believed to be involved in the generation of pain and/or inflammation, and does not have negatively adverse effects on other neural systems.
Local administration of a botulinum toxin, can provide a high, local therapeutic level of the toxin. A controlled release polymer capable of long term, local delivery of a Clostridial toxin to a target muscle permits effective dosing of a target tissue. A suitable implant, as set forth in U.S. Pat. No. 6,306,423 entitled “Neurotoxin Implant”, allows the direct introduction of a chemotherapeutic agent to a target tissue via a controlled release polymer. The implant polymers used are preferably hydrophobic so as to protect the polymer incorporated neurotoxin from water induced decomposition until the toxin is released into the target tissue environment.
Local administration of a botulinum toxin, according to the present invention, by injection or implant to a target tissue provides a superior alternative to systemic administration of pharmaceuticals to patients to alleviate a headache.
The amount of a botulinum toxin selected for local administration to a target tissue according to the present disclosed invention can be varied based upon criteria such as the severity of the pain or type of headache being treated, the extent of muscle tissue to be treated, solubility characteristics of the neurotoxin toxin chosen as well as the age, sex, weight and health of the patient. For example, the extent of the area of muscle tissue influenced is believed to be proportional to the volume of neurotoxin injected, while the quantity of the suppressant effect is, for most dose ranges, believed to be proportional to the concentration of a botulinum toxin administered. Methods for determining the appropriate route of administration and dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill in the art (see for example, Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci et al., 14th edition, published by McGraw Hill).
The following non-limiting example provides those of ordinary skill in the art with specific preferred selection and treatment methods within the scope of the present invention and are not intended to limit the scope of the invention. In the following examples various modes of non-systemic administration of a Clostridial neurotoxin can be carried out. For example, by intramuscular injection, subcutaneous injection or by implantation of a controlled release implant.
A female patient, 48 years old complained of migraine headaches since the age of 12 and reported migraine family history. Before botulinum toxin administration she suffered 20 migraine attacks a month, each lasting a day with pain intensity of 7 on a scale of 0 to 10. She described the pain as feeling “like a very tight band across my forehead”, which was viewed as an outside to the inside the head pain, and she was therefore classified as having an imploding headache pain. The patient can be administered various doses of a botulinum toxin at various injection sites. For example, Botox can be administered at a dose of about 5 Units at multiple (32) sites into the frontalis, glabellar, temporalis, occipitalis, splenius capitus, semispinalis, trapezius muscle groups for to a total dose of about 160 Units After Botox administration the patient experienced only one migraine attack a month with a pain intensity of 3 on a scale of 0 to 10.
A botulinum toxin type B, C, D, E, F or G can be substituted for the botulinum toxin type A used above.
Seven patients with migraine headache who responded to administration of a botulinum toxin to treat their migraine and seven additional patients with migraine did not respond or who responded poorly to administration of a botulinum toxin to treat their migraine were included in this study. Significantly, it was determined through patent interviews that the non-responders were all patients who reported that their migraine included exploding headache pain (that is reported a perception by the patient of having an inside to outside headache pain) with little or no imploding headache pain, and that the responders were all patients who reported that their migraine included imploding headache pain (that is reported a perception by the patient of having an outside to inside headache pain) with little or no exploding headache pain.
Each patient was administered a botulinum toxin type A (BOTOX®). The patients can be administered various doses of a botulinum toxin at various injection sites. For example, about 5 units of Botox can be injected into injection sites in the frontalis, glabellar, temporalis, occipitalis, splenius capitus, semispinalis, and trapezius muscle groups. The total dose per patient can be between about 180 and about 220 Units. The results are shown in Table 1, where “Change in HA Frequency Month” means the change in how many days a month the patient has a headache after botulinum toxin administration; an arrow means there was a change to the number of days a month with headache to the number shown to the right of the arrow. “HA Duration (Days)” means how long each headache lasts. “Change in Pain Intensity” means the intensity of the headache pain as perceived by the patients on a scale of 0 to 10. “NC” means no change.
As shown by Table 2, most non-responders did not have a change in monthly headache frequency, duration of headache or pain intensity after botulinum toxin administration. As also shown by Table 1, most responders did have a change in monthly headache frequency, duration of headache or pain intensity after botulinum toxin administration.
We carried out a study to identify neurological symptoms that would tag episodic-migraine patients who respond prophylactically to a botulinum toxin type A treatment. Quite a few migraine patients have noticed a considerable decrease in attack frequency following botulinum toxin injections. Some migraineurs (patients with migraine) however do not experience such improvement after a botulinum toxin type A administration. This study determined a marker that can tease out prospective responders from non-responders.
Patients were interviewed in the clinic for detailed migraine symptoms and medical history. Patients experiencing a >75% reduction in attack frequency within 3 months of botulinum toxin type A treatment were selected as responders. Patients who showed no change in attack frequency were selected as non-responders. The interviewer had no knowledge of the patient's response to the botulinum toxin type A treatment before the interview was completed.
Responders (n=35) experienced significant drops in the number of attacks/month (12.7±1.7 before botulinum toxin type A vs. 1.5±0.4 after treatment), attack duration (1.7±0.2 vs. 0.5±0.1 days), and headache intensity (9.1±0.2 vs. 4.4±0.6 pain score). Non-responders (n=24) yielded identical values before and after treatment: 10.5±1.6 vs. 10.7±1.6 attacks/month; 1.4±0.2 vs. 1.4±0.2 days/attack; 8.0±1.4 vs. 7.8±0.4 pain score. No difference was found between responders and non-responders across the full array of the classic migraine symptoms. However, there was one clear difference between the two groups: 92% of non-responders described their headache as exploding (extreme pressure inside the head) whereas 89% of the responders described their headache as imploding (extreme pressure outside the head) or ocular (extreme pressure behind the eyeball). We conclude therefore that migraine with imploding or ocular headache was highly associated with successful prevention of attacks using a botulinum toxin type A and that migraine with exploding headache was highly associated with failure to block migraine attacks when a botulinum toxin type A was administered.
Patients have reported symptoms and effects of ocular migraine headache pain as follows: “I want to take a spoon and pull out my eye”; “my eyes are popping out”; “someone is jabbing a knife into my eye and I want to take my eye out”, and; “someone is pushing a finger into my eye”. A common aspect of ocular headache pain (synonymously ocular migraine headache pain) is a feeling of pain in the eye, or in the eye socket or adjacent tissue. In one prospective, double blind study of patients with migraine which included two patients with ocular headache pain, both these migraine patients with ocular headache pain responded (became headache free) after administration of a botulinum toxin (BOTOX). Additionally, in a second retrospective, triple blind study (blinded as to investigator, patient and attending physician) of patients with migraine which included eight patients with ocular headache pain, all eight of these migraine patients with ocular headache pain responded (became headache free) after administration of a botulinum toxin (BOTOX).
The results from Examples 1-4 can be summarized in
A female patient, 32 years old complains of migraine headaches. Before botulinum toxin type B administration she suffers about 25 migraine attacks a month, each lasting most of a day with pain intensity of 8 on a scale of 0 to 10.
Based on her pain perception she is classified as having an imploding headache pain. After administration of a botulinum toxin type B (1200 units into the frontals and glabellar muscles, 800 units into the occipitalis muscles and 200 units into the trapezius muscle) she experiences only one migraine attack a month with pain intensity of 1 out of 10.
All references, articles, patents, applications and publications set forth above are incorporated herein by reference in their entireties. Although the present invention has been described in detail with regard to certain preferred methods, other embodiments, versions, and modifications within the scope of the present invention are possible. For example, each of the botulinum neurotoxins A, B, C, D, E, F and G can be effectively used in the methods of the present invention.
Accordingly, the spirit and scope of the following claims should not be limited to the descriptions of the preferred embodiments set forth above.
